Large-Scale Analysis of Gene Expression Data Reveals a Novel Gene Expression Signature Associated with Colorectal Cancer Distant Recurrence

Abstract

Colorectal cancer (CRC) is the fourth-ranked cause of cancer-related deaths worldwide. Despite recent advances in CRC management, distant recurrence (DR) remains the major cause of mortality in patients with preoperative chemotherapy and radiotherapy, underscoring a need to precisely identify novel gene signatures for predicting the risk of systemic relapse. Herein, we integrated two independent CRC gene expression datasets: the GSE71222 dataset, including 26 patients who developed DR and 126 patients who did not develop DR, and the GSE21510 dataset, including 23 patients who developed DR and 76 patients who did not develop DR. Our data revealed 37 common upregulated genes (fold change (FC) ≥ 1.5, P < 0.05) and three common downregulated genes (FC ≤ 1.5, P < 0.05) between DR and non-recurrent patients from the two datasets. We subsequently validated the upregulated gene panel in the Cancer Genome Atlas CRC datasets (379 patients), which identified a five-gene signature (S100A2, VIP, HOXC6, DACT1, KIF26B) associated with poor overall survival (OS, log-rank test P-value: 1.19 × 10-4) and poor disease-free survival (DFS, log-rank test P-value: 0.002). In a Cox proportional hazards multiple regression model, the five-gene signature and tumor stage retained their significance as independent prognostic factors for CRC DFS and OS. Therefore, our data identified a novel DR gene expression signature associated with worse prognosis in CRC.

Fig 1. Genes associated with CRC distant recurrence (DR).

Heatmap depicting the expression levels of differentially expressed genes (1.5 fold changes and P ≤ 0.05) between DR and non-recurrent (NR) CRC patients from the GSE71222 (a) and GSE21510 (b) datasets. Each column represents an individual sample and each row represents a single transcript. The expression level of each mRNA in a single sample is depicted according to the color scale. (c) Venn diagram depicting the common upregulated genes between DR and NR CRC samples from the GSE71222 and GSE21510 datasets. (d) Pie chart illustrating the distribution of the top 5 pathway designations for the 44 common upregulated transcripts from (c). The pie size corresponds to the number of matched entities.

Fig 2. Validation of the distant recurrence (DR) gene panel in the TCGA dataset.

(a) OncoPrint of the DR five-gene signature in the TCGA CRC dataset. Alteration in the expression of different members of the five-gene signature (rows) in relation to each sample (columns). Relationships to overall and disease-free survival are also shown. CRC cases with upregulated expression of the DR signature showed worse overall (b) and disease-free (c) survival than cases with lower expression. (d) Network view of the VIP/DACT1/S100A2 neighborhood in CRC. VIP, DACT1, and S100A2 are seed genes (indicated with thick borders), and all other genes were identified as altered in CRC.